. The long term goal of this proposal is to develop systemic antifungal agents with minimal toxicity and preferable capabilities of being delivered orally. The immediate focus, however, is to design, synthesize and evaluate cryptolepine analogues, in order to understand the structural characteristics and requirements for its antifungal activity. Optimism to use cryptolepine as the lead compound derives from its potency, water solubility, low toxicity and broad spectrum of activity against opportunistic infections (OIs) associated with AIDS. Several structural analogues of cryptolepine will be synthesized to delineate the structural features in the quindoline nucleus that contribute to activity and any toxicities associated with the drug. This information will be incorporated into a computer assisted drug design of more potent and less toxic compounds as alternatives to Amphotericin B and 5 Fluorocytosine (5 FC). Graphical computer displays will aid visualization and comparison of the 3 dimensional structures of the proposed compounds and other natural products with similar activity. The active analog approach will be utilized in the identification and selection of pharmacophoric groups associated with antifungal activity. Each synthetic compound will be characterized by IR, NMR and elemental analysis, and then screened for antifungal activity using agar well diffusion assays. Promising new compounds will subsequently undergo an in vitro evaluation using a two fold serial broth dilution assay. In vivo evaluation for antifungal activity, toxicity and mechanism of action are planned as a follow up to this proposal.